Post Orthotopic Heart Transplantation Research Articles

Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine

ObjectiveThis study investigates the efficacy of using a long-acting insulin analog, along with the infusion of regular insulin, in achieving appropriate glycemic control and correcting lactic acidosis in patients post orthotopic heart transplant who demonstrate severe lactic acidosis and insulin resistance.MethodsThis was a retrospective study of two cohorts (IRB FLA 20-003) of patients post orthotopic heart transplant with severe lactic acidosis and insulin resistance who were admitted to a tertiary intensive care unit and treated with (group 1) or without long-acting insulin analog (group 2) within the first 24 h of admission to the intensive care unit. Insulin resistance is defined as the requirement for intravenous regular insulin infusion of more than 20 units/h without the ability to achieve appropriate serum glucose level (120–180 mg /dL). Severe lactic acidosis is defined as arterial lactic acid of more than 10 mmol/L. The following parameters were investigated: time to correct lactic acidosis, duration of postoperative mechanical ventilation, the need for periprocedural mechanical circulatory support, and 28-day mortality.ResultsThe 28-day mortality was zero in both groups. Two patients required periprocedural mechanical support in group one, and ten patients required mechanical support in group two (RR = 0.224, 95%, confidence interval 0.052–0.95, Z = 2.029, p = 0.042). Three patients required tracheostomy in group one, and four patients required tracheostomy in group two (RR 0.84, 95 confidence interval 0.20–3.48, Z = 0.23, P = 0.81). Wilcoxon rank-sum test was used to compare time to correct lactic acidosis, with lactic acid resolution being faster in group one (X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}1 = 19.7 h, SD ± 12.6 h X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}2 = 29.3 h, SD ± 19.6 h, Z-value − 2.02, p-value 0.043). The duration of mechanical ventilation was less in group one (X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}1 = 29 h, SD ± 12.7 h, X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}2 = 55.1 h, SD ± 44.5 h, Z-value: − 1.92, p-value 0.05).ConclusionAdministration of low-dose long-acting insulin glargine led to the resolution of the lactic acidosis, insulin resistance, and decreased requirements for pressor and inotropic support, which led to decreased need for mechanical circulatory support.

Preoperative Amiodarone and Primary Graft Dysfunction in Heart Transplantation.

Preoperative amiodarone effects on postorthotopic heart transplant (OHT) outcomes remain controversial. The purpose of this study was to determine the effect of cumulative pre-OHT amiodarone exposure on severe primary graft dysfunction (PGD). We retrospectively reviewed adult OHT recipients between August 2012 and June 2018. Primary outcome was severe PGD in patients receiving amiodarone at 3, 6, and 12 months prior to OHT compared with those not receiving amiodarone. Secondary outcomes included intensive care unit (ICU) and hospital length of stay, duration of mechanical ventilation, early graft failure (EGF), mortality at 3, 6, and 12 months post-OHT, and 30-day incidence of postoperative tachyarrhythmias, bradycardia, permanent pacemaker implantation, and rejection. Incidence of severe PGD was 12.5% in those who received amiodarone compared to 6.8% in those who did not (14 vs 6, P = 0.18). Cumulative preoperative amiodarone significantly increased the odds of severe PGD at 3 months (odds ratio [OR]: 1.03; 95% confidence interval [CI]: 1.001-1.06; P = 0.044) and 6 months (OR: 1.02, 95% CI: 1.003-1.044; P = 0.024) in a multivariate logistic regression. Patients on amiodarone had significantly higher rates of postoperative bradycardia (13.4% vs 4.5%, P = 0.03). A trend toward increased PGD was present in patients receiving preoperative amiodarone. This finding combined with the regression showing significantly increased odds of PGD with increasing 3 and 6 month cumulative amiodarone dose is clinically concerning. Escalation of care with pacemaker implantation was required more frequently in patients on pre-OHT amiodarone.

300 Impact of the type of mechanical circulatory support (MCS) prior to transplant on development of post-orthotopic heart transplantation (OHT) infections

OBJECTIVES/GOALS: In 2018, the United Network for Organ Sharing began prioritizing patients on temporary MCS over those on durable MCS for OHT in an effort to prioritize sicker patients and decrease waitlist mortality. We explored the impact of this change by examining if the type of MCS prior to transplant affects the risk of post-transplant infection. METHODS/STUDY POPULATION: We will conduct a retrospective cohort study of approximately 350 patients that have undergone OHT at Tufts Medical Center between January 2014 and July 2021 who survived at least 72 hours post-transplant and have minimum post-transplant follow-up of one year or time to death if before one year. Chart review will determine the type of MCS in place prior to transplant and the occurrence of infections within one year of transplant. Data will also be collected on patient’s age, sex, medical comorbidities, lab values, and open chest management practices. We will examine differences in the incidence rates of a composite outcome (blood stream infection, invasive fungal infection, skin and soft tissue infection of device sites, and mediastinitis) between patients that were on temporary versus durable MCS. RESULTS/ANTICIPATED RESULTS: We anticipate that this study will show a greater frequency of infections of all types in patients that received temporary as compared with durable mechanical circulatory support prior to transplantation. We will use Cox proportional hazards survival models to model multivariable relationships for predictors of infection. DISCUSSION/SIGNIFICANCE: This study will provide insights into the magnitude and type of infectious complications that patients experience after OHT and the impact that type of MCS and other factors have on their outcomes. The data obtained may have implications for choice of mechanical device prior to undergoing OHT surgery as well as antimicrobial prophylaxis.

Immune cell function assay and T lymphocyte counts lack association with rejection or infection in pediatric heart transplant recipients.

Immune cell function assay (ICFA) and CD3 lymphocyte counts have been considered to be useful in discerning the overall intensity of immunosuppression in pediatric orthotopic heart transplant (OHT) recipients. The aim of this retrospective analysis was to evaluate trends of ICFA and CD3 lymphocyte counts and their association with adverse outcomes post-OHT. A total of 381 ICFA and 493 CD3 laboratory values obtained in 78 patients within six months post-OHT were analyzed. There were 14 patients treated for biopsy-proven acute rejection, four of whom had ISHLT grade 2R/3A rejection. In patients with rejection versus those without, CD3 and ICFA values were 122 (IQR 74.5-308) cells/mm2 and 224.5 (IQR 132-343.5) ng/ml compared to 231.8 (IQR 68-421) cells/m2 and 191 (IQR 81.5-333) ng/mL (p=NS for both). Twenty-six patients had at least one detectable cytomegalovirus or Epstein-Barr virus DNAemia within the study timeframe. In patients with viremia versus those without, CD3 and ICFA values were 278.5 (IQR 68-552) cells/mm2 and 130 (IQR 48-284) ng/ml compared to 195 (IQR 74.5-402.5) cells/mm2 and 212 (IQR 89-342) ng/ml (p=NS for both). No association was found between these immune markers and adverse outcomes. In the absence of larger pediatric studies justifying the role of these tests in identifying elevated risk profiles post OHT, we do not recommend their routine use.

Abstract 11218: The Variation of Left Heart Size Based on Donor and Recipient Sex and Its Impact on Outcomes After Orthotopic Heart Transplant

Introduction: The impact of sex mismatch on outcomes after orthotopic heart transplant (OHT) remains unclear. We aimed to evaluate the change in left ventricle (LV) size based on donor and recipient sex and examine its association with the outcomes. Methods: This was a single institution, retrospective study among OHT recipients between Jan 2015 and Sept 2020. Patients were excluded if they were<18 years old, received OHT for congenital heart disease, had follow-up<6 months or missing donor variables. We collected donor (D) and recipient (R) clinical and echocardiographic characteristics. First and last echo post OHT were collected at least 2 months apart. Donor data was extracted from UNOS database. Primary outcome was the variation in donor heart size based on sex at first and last echo after transplant and the difference in survival or HF hospitalization. Statistical analysis (T test) was performed using Stata 15.1. Results: Among 156 reviewed patients, N=68 were included. Female (F) recipients (R) median age was 51±16 y, 25% were African-American (AA) while male (M) recipients median age was 56±12y and 19% were AA. Pre-transplant, MR had a higher RV and LV predicted heart mass and higher CO, CI by Fick. Aside from a higher prevalence of hypertension in MR, there was no difference in baseline characteristics. OHT allocation was MD/MR (66%); FD/FR (18%); FD/MR (4%); MD/FR (12%). LVEDD was bigger in MR on the first echo and remained on last echo post-transplant. There was no difference in degree of variation of LV parameters (LVEDD, LVESD, LV thickness) in MD/MR vs FD/MR and FD/FR vs MD/FR. Compared to sex matched, sex mismatched cohort had a non-significant trend towards a bigger degree of variation in LV size at first (-9% ± 10% vs -2% ± 21%;p=0.14) and last echo (-8% ± 12% vs -4% ± 14%;p=0.1).There were 18% (66% acute cellular rejection) cases of rejection split in half between sex matched and mismatched cohort. At a follow-up duration up to 6 years, 25% (N=17/68) of patients did not survive. There was no difference in survival or HF hospitalization in MR vs FR, in sex matched vs sex-mismatched. Conclusions: This is one of the first studies to examine the change in LV size and its impact on outcomes post OHT. The potential impact of LV behavior in M vs F is worth exploring on larger cohorts.

Aortic valve replacement using On-X valve in a child postorthotopic heart transplantation.

A 20-month-old girl presented with severe dilated cardiomyopathy and decompensated congestive cardiac failure. Despite escalating inotropic and mechanical ventilation support, she required placement on extracorporeal membrane oxygenation and transfer to the transplant centre in Newcastle, England. She was placed on biventricular assist device and then Berlin Heart but failed to show any recovery of ventricular function. She underwent orthotopic heart transplantation at 2 years of age. She developed bacterial endocarditis with Enterococcus faecalis resulting in severe aortic valve regurgitation requiring aortic valve replacement with a 19 mm On-X valve (Airtivion) 11 days after her transplant. Given the size of the donor heart, it was possible to implant a 19-mm valve in this 12 kg child with minimal risk of patient prosthesis mismatch. She was anticoagulated with warfarin (On-X valve INR 2-3 for first 3 months; INR 1.5-2.0 thereafter). Although she suffered several other post-operative complications, including malabsorption, nasojejunal feeding, liver dysfunction, vertebral fractures, renal impairment and renal calcification, and need for repeat opening of her tracheostomy site following her initial decannulation, her aortic valve function has remained stable.

Transplant-associated thrombotic microangiopathy: a rare but deadly complication post orthotopic heart transplantation.

Transplant-associated thrombotic microangiopathy: a rare but deadly complication post orthotopic heart transplantation.

Safety and Efficacy of SGLT2i Post Orthotopic Heart Transplantation

<h3>Purpose</h3> Diabetes mellitus is common after orthotopic heart transplantation (OHT) due to steroid-induced hyperglycemia. Traditionally, it has been treated using parenteral insulin therapy. The use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in OHT recipients is not well established. <h3>Methods</h3> A retrospective chart review was performed on all the patients who underwent OHT at our center to identify patients on SGT2i post OHT. Clinical outcomes pre and post SGLT2i therapy were compared using the student t-test. <h3>Results</h3> Out of the 455 patients who had OHT at our single institution, 26 patients were on SGLT2i post OHT (1 patient was dual organ recipient - heart and liver transplant). The baseline characteristics are reported in Table 1. The median days from OHT to initiation of SGLT2i was 780 days (range 40-4986 days), and the median duration of therapy post-OHT was 169 days (range 38-2474 days). There was a statistically significant improvement in the average hemoglobin A1c, weight, and body mass index after starting SGLT2i (Results table). There was a trend towards improving renal function. There was no incidence of systemic infection, hypoglycemia, amputation, or euglycemic diabetic ketoacidosis while on SGLT2i. Two patients were able to discontinue insulin therapy after starting SGLT2i. There was no incidence or progression of cardiac allograft vasculopathy during the therapy. Two patients experienced graft rejection (1Antibody Mediated Rejection and 1 Acute Cellular Rejection) with drop in left ventricular systolic function that recovered after appropriate treatment. <h3>Conclusion</h3> SGLT2i can be used safely in OHT recipients. The renal protective mechanism of SGLT2i could be helpful to combat the nephrotoxicity of calcineurin inhibitors (CNI) used for immunosuppression and help prolong the use of CNI. Further randomized studies are required to explore the complete benefits of SGLT2i in OHT recipients

Challenges of Treating Late Onset Severe Antibody Mediated Rejection Post Orthotopic Heart Transplant

<h3>Introduction</h3> Outcomes of severe antibody mediated rejection (AMR) post orthotopic heart transplant (OHT) are often poor & management a challenge. <h3>Case Report</h3> A 50-year-old multiparous female with stable donor specific antibodies (DSAs) presented with cardiogenic shock (CS) & severe left ventricular (LV) dysfunction 4 years post OHT. Maintenance immunosuppressants (IS) included tacrolimus, mycophenolate & prednisolone with good adherence. Urgent endomyocardial biopsy (EMB), coronary angiogram & right heart catheterisation were performed. Progression to SCAI Stage D shock necessitated venoarterial extracorporeal membrane oxygenation (VA ECMO) within 24 hrs. Based on clinical presentation, the patient was treated with methylprednisolone, intravenous immunoglobulin (IVIG) & IV thymoglobulin alongside hemodynamic & other organ support (dialysis, ventilation). EMB confirmed pAMR3 fulfilling criteria for severe AMR together with CS & raised DSAs. Within days the patient's cardiac output improved allowing removal of VA ECMO. Following MDT consensus given persistent graft dysfunction & DSAs an AMR specific regimen of plasmapheresis, IVIG & rituximab were administered resulting in significant improvement in LV function & DSAs. A serious consequence of high dose IS was severe CMV reactivation (CMV peak 18,000 copies/ml). Successful treatment with IV ganciclovir caused leukopenia requiring mycophenolate cessation. Fortunately our patient survived to discharge day 152 post admission with graft recovery & excellent functional capacity. Ongoing management remains a challenge due to severe CAV & balancing risks associated with high dose IS with AMR recurrence. <h3>Summary</h3> This case highlights the importance of urgent evaluation including EMB, hemodynamic support & targeted anti-rejection therapy in patients post OHT with severe allograft dysfunction. It exemplifies challenges when treating severe AMR illustrating the importance of a collaborative team approach for successful outcomes.

Characteristics and Outcomes of Patients with Cardiac Amyloidosis Requiring Orthotopic Heart Transplantation

<h3>Purpose</h3> It has been suggested that patients with cardiac amyloidosis can have similar outcomes post orthotopic heart transplantation (OHT) compared to non-amyloid cardiomyopathies. Our aim is to report characteristics and outcomes after OHT in patients with cardiac amyloidosis in a large single-center quaternary university hospital. <h3>Methods</h3> We performed a retrospective chart review of all patients with AL amyloid who underwent OHT from January 2017 to October 2021. Kaplan-Meier method was used to assess time to death compared to non-amyloid cardiomyopathies. <h3>Results</h3> Analytic sample was 280 patients, with a median follow up of 1.86 years. We had 16 patients with amyloid, aTTR amyloid was the more prevalent (50%), followed by AL (44%) and one case of ApoA1. Our cohort had a male predominance (75%), with a mean age of 61.7 years. Carpal tunnel was the most prevalent extracardiac involvement (56%), followed by renal (31%), peripheral neuropathy (31%), autonomic neuropathy (19%) and gastrointestinal (19%). Mean Vo2 max was of 14ml/min/kg; the median time on the waiting list was 35 days. The pathological light chain was Lambda in 86% of those with AL with a median difference in free light chains of 280 mg/dL. In patients with ATTR, wild type was the most prevalent (63%) compared to 38% with the V122I mutation. We did not observe mortality, graft failure or episode of antibody-mediated rejection. There was no statistical difference in survival at 3-years between amyloid (100%) and non-amyloid (93.4%) patients, Wilcoxon p-value = 0.32. Acute cellular rejection requiring treatment was observed in 2 patients, with a mean time to rejection of 100 days. Multifactorial progression of nephropathy was seen in 31% of patients. Progression of neuropathy was seen in 25% of patients and only one patient reported GI symptom progression. <h3>Conclusion</h3> Patients with cardiac amyloid undergoing OHT with limited extracardiac involvement had comparable survival to patients with non-amyloid cardiomyopathies.

Characteristics of early pleural effusions after orthotopic heart transplantation: comparison with coronary artery bypass graft surgery.

ObjectivesPleural effusions appearing within the first 30 postoperative days following coronary artery bypass grafting (CABG) are classified as early and believed to be directly related to the surgery. The characteristics of such effusions are well-described. Orthotopic heart transplantation is also known to be complicated by pleural effusions; however, their characteristics have not been systematically reported. We assessed the features of early postoperative pleural effusions after heart transplantation and compared them to those of early effusions following CABG.MethodsWe retrospectively collected demographic, clinical, and laboratory data for patients who underwent either orthotopic heart transplantation (study group) or CABG (comparison group) at our institution and whose postoperative course within 30 days was complicated by new or worsening pleural effusion that prompted drainage. Patients subjected to analysis consisted only of those with sufficiently complete laboratory profiles to permit adequate characterization of the nature of their pleural fluid.ResultsOut of 251 orthotopic heart transplant recipients, seven (2.8%) were found to have sufficiently complete pleural fluid results to be included in the study group. Out of 1,506 patients who underwent CABG, 32 (2.1%) had sufficiently complete pleural fluid results and formed the comparison group. The radiological appearance of pleural effusions in both groups was similar: bilateral in at least half and exclusively moderate to large. Effusions complicating both surgeries were exudative in close to 90% of cases. For those with available leukocyte differential counts, the pleural fluid of the post-orthotopic heart transplantation group was more often neutrophilic (3/5, 60%), whereas the fluid of the post-coronary artery bypass grafting group was more often lymphocytic (22/32, 69%) and tended to be hemorrhagic (median RBC count 33,000 cells/µL vs. 10,000 cells/µL). None of the comparisons of pleural fluid characteristics between the two groups reached statistical significance.ConclusionsThis small, descriptive study is the first to systematically report the fluid characteristics of pleural effusions complicating orthotopic heart transplantation within the first 30 postoperative days and to compare this group to those who developed effusions after CABG. Our findings revealed both similarities and differences in the pleural fluid characteristics between these two types of patients.

Withdrawal: Characteristics of early pleural effusions after orthotopic heart transplantation: comparison with coronary artery bypass graft surgery.

Anant Jain (2021) Characteristics of early pleural effusions after orthotopic heart transplantation: comparison with coronary artery bypass graft surgery, (https://doi.org/10.4081/monaldi.2021.1740). The above article from the Monaldi Archives for Chest Disease published online on 24 November 2021, has been withdrawn by agreement between the journal's Editors-in-Chief, the Authors and PAGEPress Scientific Publications. This action has been agreed upon due to an administrative error by the publisher which caused the article to be published as an Accepted Article. The author is not responsible for this error. The publisher regrets any confusion this error may have caused.

Coronary imaging of cardiac allograft vasculopathy predicts current and future deterioration of left ventricular function in patients with orthotopic heart transplantation.

Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) improve sensitivity of cardiac allograft vasculopathy (CAV) detection compared to invasive coronary angiography (ICA), but their ability to predict clinical events is unknown. We determined whether severe CAV detected with ICA, IVUS, or OCT correlates with graft function. Comparison of specific vessel parameters between IVUS and OCT on 20 patients attending for angiography 12-24 months post-orthotopic heart transplant. Serial left ventricular ejection fraction (EF) was recorded prospectively. Analyzing 55 coronary arteries, OCT and IVUS correlated well for vessel CAV characteristics. A mean intimal thickness (MIT)OCT >.25mm had a sensitivity of 86.7% and specificity of 74.3% at detecting Stanford grade 4 CAV. Those with angiographically evident CAV had significant reduction in graft EF over 7.3 years follow-up (median ΔEF -2% vs +1.5%, P=.03). Patients with MITOCT >.25mm in at least one vessel had a lower median EF at time of surveillance (57%vs 62%, P=.014). Two MACEs were noted. Imaging with OCT correlates well with IVUS for CAV detection. Combined angiography and OCT to screen for CAV within 12-24 months of transplant predicts concurrent and future deterioration in graft function.

THE SPORADIC DYSRHYTHMIA OF TACROLIMUS IN AN ORTHOTOPIC HEART

TOPIC: Cardiovascular Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: Immunosuppressive therapy is essential for organ transplanted patients. One such broadly used agent is the commonly used macrolide antibiotic tacrolimus. Tacrolimus has several well-known adverse effects including nephrotoxicity, neurotoxicity, infection, diarrhea. Reports of supraventricular tachycardia as a side effect of tacrolimus are rare. CASE PRESENTATION: We present a 48-year-old male with a history of non-ischemic cardiomyopathy status post orthotopic heart transplant who presented to the hospital due to sudden onset palpitations with mild diaphoresis which lasted 30 minutes in duration. Patient reported some mild diaphoresis but no shortness of breath, chest pain, lightheadedness, or dizziness. The patient stated that he had been experiencing episodes of tachycardia for the last few months but none that had persisted to this extent. He reported medication compliance. His vitals were Temp 98.4, BP 140/88, HR 260, RR 20. After review of his EKG, he was diagnosed with supraventricular tachycardia (SVT) (referenced EKG is after adenosine administration). The patient was hospitalized a few months prior to admission for COVID 19 infection and acute pulmonary embolism. His transplant antirejection regimen was changed from sirolimus to tacrolimus during this prior hospitalization due to the increased risk of thrombosis associated with sirolimus in view of the recognized prothrombic effects of COVID-19. Incidentally, the patient started experiencing sporadic episodes of tachycardia since this change in his medication regimen. In the emergency department, diagnostic studies such as troponins, CBC, BMP, magnesium, hepatic panel, TSH, CMV DNA were within normal parameters for the patient. Tacrolimus blood concentration level was found to be 17 with a goal normal level between 4 to 6. The patient had a right/left heart catheterization with endomyocardial biopsy which showed no evidence of coronary artery vasculopathy or acute cellular rejection, thereby ruling out other potential causes of his SVT. His tacrolimus dose was subsequently decreased with significant improvement in the frequency of his symptoms and no further reported episodes of SVT (with further tacrolimus levels not exceeding 7). DISCUSSION: The mechanism by which tacrolimus leads to SVT is not well understood. One purported mechanism is through the inhibition of the calcineurin-calcium-calmodulin complex. Calcium calmodulin is coincidentally also used by smooth muscle cells to contract. It is thought that by inhibiting this system, there is a subsequent increase in vasodilation which leads to the increased sympathetic and adrenergic response, thereby increasing the risk of arrhythmias such as SVT. CONCLUSIONS: Incessant dysrhythmias caused by tacrolimus can be life-threatening, whereby we seek to raise awareness of the importance of carefully monitoring patients on this drug. REFERENCE #1: Kim BR, Shin HS, Jung YS, Rim H. A case of tacrolimus-induced supraventricular arrhythmia after kidney transplantation. Sao Paulo Med J. 2013;131(3):205-207. doi:10.1590/1516-3180.2013.1313472 REFERENCE #2: Pires SDS, Oliveira R, Moradas-Ferreira P, Mendes MV. The Onset of Tacrolimus Biosynthesis in Streptomyces tsukubaensis Is Dependent on the Intracellular Redox Status. Antibiotics (Basel). 2020;9(10):703. Published 2020 Oct 15. doi:10.3390/antibiotics9100703 REFERENCE #3: Wojciechowski D, Wiseman A. Long-Term Immunosuppression Management: Opportunities and Uncertainties [published online ahead of print, 2021 Apr 14]. Clin J Am Soc Nephrol. 2021;CJN.15040920. doi:10.2215/CJN.15040920 DISCLOSURES: No relevant relationships by Jamarcus Brider, source=Web Response No relevant relationships by Ahamed Khalyfa, source=Web Response No relevant relationships by Navkiran Randhawa, source=Web Response

Pathophysiology of severe primary graft dysfunction in orthotopic heart transplantation.

A series of insults on the donor heart result in pathophysiological changes that manifest as primary graft dysfunction (PGD) post-orthotopic heart transplantation. The objectives of this study were: (i) describe the pathophysiology of severe PGD using an established cardiovascular model; and (ii) the evolution of the pathophysiology during recovery from severe PGD. Hemodynamic data from 20 consecutive patients with severe PGD (need for mechanical circulatory support, MCS) at baseline (T0), 6h (T6) and "recovery" (explant of support), and 20 consecutive patients without severe PGD were used to model the pathophysiology using the cardiovascular model described by Burkhoff and Dickstein. There was a progressive (from T0 to T6) up- and leftward shift in the diastolic pressure-volume relationship, especially of the right ventricle (RV), resulting in reduced capacitance. RV end-systolic elastance (Ees) was significantly elevated in severe PGD but preload-recruitable stroke work (PRSW) was significantly lower compared to patients without severe PGD. "Recovery" (after liberation from MCS) was associated with improvement in RV Ees, chamber capacitance and PRSW, although they remained significantly lower than patients without severe PGD. Severe PGD of the dominant right heart failure phenotype is characterized by reduced chamber capacitance, increased "stiffness" and impaired contractility. Complete normalization was not required for successful weaning of MCS.

Dueling Malignancies: A Rare Instance of Both Kaposi Sarcoma and Cardiac Plasmacytoma in a Patient Post OHT

<h3>Introduction</h3> Judicious immunosuppressive therapy is important to balance immune tolerance of the donor organ, while minimizing the risk of infection and malignancy. This case highlights the development of two unusual malignancies post orthotopic heart transplant (OHT). <h3>Case Report</h3> A 69 year old male, with a history of ischemic cardiomyopathy and no prior history of hematological malignancies underwent OHT. His post-transplant course was complicated by multiple infectious complications, leading to discontinuation of mycophenalate mofetil and he was maintained on an immunosuppressive regimen of tacrolimus and low-dose prednisone. Two years post OHT he noticed the development of a nodule on his 2nd right toe. Biopsy revealed Kaposi Sarcoma (KS). The patient underwent a total body PET scan and was found to have bilateral hypermetabolic inguinal lymph node involvement confirmed as KS by biopsy. His tacrolimus goal was lowered and he was treated with 8 cycles of paclitaxel, which resulted in complete PET resolution. One year later as part of a routine endomyocardial biopsy the patient was found to have a population of plasma cells with kappa restriction that were EBV negative. A TTE showed a structurally normal heart without evidence of mass/tumor. Magnetic resonance imaging showed late gadolinium enhancement in the inferior, basal inferolateral and anterolateral segments. Workup for MGUS/Multiple Myeloma was unrevealing. The diagnosis was thought to be a solitary cardiac plasmacytoma. The decision was made to further minimize immunosuppression to single agent tacrolimus with a goal tac level of 4-6. <h3>Summary</h3> Kaposi Sarcoma and cardiac plasmacyotoma are infrequent to rare tumors encountered in the transplant population. The literature on treatment for patients who develop malignancy post transplantation is sparse, with the majority of anecdotal evidence suggesting that reducing the level of baseline transplant immunosuppression is adequate for resolution of the underlying malignancy.

Risk Factors for Malignancy after Orthotopic Heart Transplant: An Analysis of the UNOS Registry

PurposeFor patients with end stage heart failure, orthotopic heart transplant (OHT) remains the definitive management. Advances in immunosuppression have led to improved long-term survival. Malignancy is an important cause of long-term morbidity and mortality with a reported rate of occurrence between 20-40% within 10 years of transplant. To date, significant evidence into mechanisms and risk profiles for post OHT malignancy is lacking. The purpose of this study is to identify patient and donor related factors associated with post OHT malignancy.MethodsWe performed a retrospective analysis of 51,218 OHT recipients captured in the United Network for Organ Sharing (UNOS) registry. Included in this analysis were adults 18 years and older who received a heart transplant between 1987 and 2019. The patients were categorized by the presence of post OHT malignancy (“yes”, “no”). Baseline characteristics were compared using chi-squared analysis for categorical variables and Mann-Whitney test for continuous variables. Logistic regressions were applied to evaluate the association between post OHT malignancy and the risk factors.ResultsWithin the study period (1987-2019), 13,060 OHT recipients (25.5%) developed a malignancy. Denovo solid tumors comprised 82% of all malignancy types. OHT recipients with malignancy were older (56 vs 50.9 years, p= <0.001), had higher proportion that were male (85% vs. 73%, p=<0.001), and White (90% vs. 68%, p= <0.001). Recipient factors associated with post OHT malignancy included older age (OR 1.05, CI 1.05-1.06, p= <0.001), White race (Asian OR 0.22, CI 0.16-0.30, p= <0.0001; Black OR 0.34, CI 0.30-0.38, p= 0.038; Hispanic OR 0.32, CI 0.27-0.39, p= 0.02), and treatment for rejection (OR 2.17, CI 1.04-4.52, p= 0.038).ConclusionIn this study, we reported the prevalence of post OHT malignancy as well as recipient and donor factors associated with post OHT malignancy. Further analysis based on malignancy subtype should be performed to aid in risk stratification and surveillance. For patients with end stage heart failure, orthotopic heart transplant (OHT) remains the definitive management. Advances in immunosuppression have led to improved long-term survival. Malignancy is an important cause of long-term morbidity and mortality with a reported rate of occurrence between 20-40% within 10 years of transplant. To date, significant evidence into mechanisms and risk profiles for post OHT malignancy is lacking. The purpose of this study is to identify patient and donor related factors associated with post OHT malignancy. We performed a retrospective analysis of 51,218 OHT recipients captured in the United Network for Organ Sharing (UNOS) registry. Included in this analysis were adults 18 years and older who received a heart transplant between 1987 and 2019. The patients were categorized by the presence of post OHT malignancy (“yes”, “no”). Baseline characteristics were compared using chi-squared analysis for categorical variables and Mann-Whitney test for continuous variables. Logistic regressions were applied to evaluate the association between post OHT malignancy and the risk factors. Within the study period (1987-2019), 13,060 OHT recipients (25.5%) developed a malignancy. Denovo solid tumors comprised 82% of all malignancy types. OHT recipients with malignancy were older (56 vs 50.9 years, p= <0.001), had higher proportion that were male (85% vs. 73%, p=<0.001), and White (90% vs. 68%, p= <0.001). Recipient factors associated with post OHT malignancy included older age (OR 1.05, CI 1.05-1.06, p= <0.001), White race (Asian OR 0.22, CI 0.16-0.30, p= <0.0001; Black OR 0.34, CI 0.30-0.38, p= 0.038; Hispanic OR 0.32, CI 0.27-0.39, p= 0.02), and treatment for rejection (OR 2.17, CI 1.04-4.52, p= 0.038). In this study, we reported the prevalence of post OHT malignancy as well as recipient and donor factors associated with post OHT malignancy. Further analysis based on malignancy subtype should be performed to aid in risk stratification and surveillance.

Experience with Posaconazole Use for Fungal Prophylaxis Immediately Post Heart Transplant

Purpose Fungal infections, specifically mucormycosis, are associated with high morbidity and mortality in the immunocompromised host. Noting a recent elevation in our rates of fungal infections, we sought to avoid mucormycosis and other post-Orthotopic Heart Transplant (OHT) fungal infections through the implementation of a systematic antifungal prophylaxis protocol. Methods Posaconazole was selected as the antifungal of choice, given provided mucormycosis coverage not provided by other azoles. We developed a Posaconazole Prophylaxis Protocol (PPP) consisting of post-operative day 1 initiation of posaconazole for a 3-month duration with a goal posaconazole trough level 1000-2000 ng/mL. At time of posaconazole discontinuation, a 2-fold dose escalation of tacrolimus dosing was implemented and bi-weekly tacrolimus levels drawn for 2 weeks to ensure goal calcineurin inhibitor levels. If strong cyp3A4 interactions or prolonged QTc prohibited posaconazole, isavuconazole was used. If early cessation of posaconazole-therapy was necessary, surveillance chest imaging was obtained with chest CT scans. Results In the 13-month period following initiation of our PPP 50 patients underwent OHT. All but one (49/50) patients received therapeutic posaconazole or in the case of drug-drug interactions, isavuconazole. 2/50 were transitioned to isavuconazole due to QT prolongation. 5/50 had posaconazole interruption with the most common reason being liver enzyme elevation (4/50). 45/50 tolerated the 3-month period on systemic azole prophylaxis. During this period there were no systemic fungal infections. Conclusion Our initial 13-month experience with a systematic 3-month antifungal prophylaxis protocol appears to be feasible, safe, and associated with uniform prevention of mucormycosis and other fungal infections that have previously proven to be highly morbid in our OHT recipients.

A Rare Case of Pancytopenia Post Heart Transplant

Introduction Hematologic malignancy following solid organ transplant is uncommon and no cases have been reported in heart transplant recipients. We present a case of acute promyelocytic leukemia (APL) after orthotopic heart transplant. Case Report 57 year-old, with dilated cardiomyopathy secondary to sarcoidosis and no history of malignancy underwent successful orthotopic heart transplant. He had one episode of cell mediated rejection which was treated with pulse dose steroids. He was on tacrolimus, cellcept and prednisone for maintenance immunosuppression. Ten months post-transplant, routine laboratory test revealed pancytopenia which was attributed to medication side effects. His cellcept and valcyte were discontinued. He received Filgrastim. Cytomegalovirus, Epstein-Barr virus, and Parvovirus B-19 infections were ruled out. He had recurrent episodes of decline in his absolute neutrophil counts and was referred to hematology. A bone marrow aspirate and smear showed left shift granulocytic maturation arrest in a promyelocytic/myelocytic stage and cells suggestive of Auer rod. FISH cytogenetics, with 23% positive for PML-RARA fusion gene, confirmed the diagnosis of APL. He was initiated on therapy with All-trans retinoic acid (ATRA). Treatment with arsenic trioxide was deferred due to concerns for cardiotoxicity. His treatment course was also remarkable for differentiation syndrome which responded to hydroxyurea and dexamethasone. Overall, he had good response to ATRA and repeat BMB showed normocellular marrow with trilineage hematopoiesis with no evidence of APL. Summary Clinicians should maintain a high degree of suspicion when patients with a history of OHT develop unexplained pancytopenia. A small case series revealed the population most commonly affected with post-transplant APL were males, with a median age of 50 years at diagnosis and within a median interval of two years post solid organ transplant. Our patient was able to achieve remission without the standard chemotherapeutic agents used to treat APL associated with cardiotoxicity such as arsenic trioxide and anthracycline. To our knowledge, this case is the first reported of post orthotopic heart transplant acute promyelocytic leukemia.

Giant Cell Myocarditis after Orthotopic Heart Transplant

<h3>Introduction</h3> Giant cell myocarditis (GCM) is a rare, T-lymphocyte driven, inflammatory disease that leads to severe myocardial dysfunction and high morbidity. De novo occurrence of GCM after orthotopic heart transplant has not been reported and there is currently little evidence to guide management. Here we present a case of new onset GCM after orthotopic heart transplant (OHT) successfully treated with high dose steroids. <h3>Case Report</h3> A 66-year-old male with end stage heart failure due to ischemic cardiomyopathy underwent OHT complicated by cytomegalovirus viremia treated with valganciclovir. His immunosuppression regimen included tacrolimus 1.5mg twice a day, mycophenolate mofetil 1g twice a day, and prednisone 15mg daily. Three months after transplant, he was found to have acute cellular rejection (grade 2R) on routine endomyocardial biopsy (EMB) and treated with pulse dose steroids. EMB one month later demonstrated a focus of giant cell and histiocytes with surrounding interstitial and perivascular inflammation, suggesting a diagnosis of GCM (Figure 1A). An echocardiogram showed an ejection fraction of 54% without wall motion abnormalities, and mildly depressed right ventricular systolic function. He was treated with methylprednisone 1g daily for three days followed by a prolonged prednisone taper in addition to sirolimus 0.5 mg daily and tacrolimus 1.5 mg twice a day. Giant cell was absent on EMB one month later, suggesting response to therapy (Figure 1B). Patient was doing well without complications six weeks after diagnosis. <h3>Summary</h3> We present a case of GCM diagnosed on EMB in a patient who is status post orthotopic heart transplant, successfully treated with high dose steroids and immunosuppressive therapy. It is important to note that there were no giant cells in his heart explant and that we cannot definitely rule out sarcoidosis. This case however highlights the importance of early diagnosis of GCM and prompt treatment. Further studies are needed to determine the optimal treatment strategy for these patients.